Hepatocellular carcinoma (HCC) represents a daunting challenge in human health, with some of the highest recorded rates of recurrence that dramatically affect patient prognosis. Although surgical techniques and therapies have improved, predicting and preventing HCC recurrence is still a clinical challenge. Recurrence is a key contributor to the low survival rates for HCC. Only about 30% of HCC patients receive potentially curative treatments (resection, liver transplantation, or ablation), yet 30-50% experience recurrence within three years [
1]. The failure to accurately recognize which patients are at high risk of recurrences prevent optimal management strategies. Due to the insufficient sensitivity and specificity of α-fetoprotein (AFP), AFP-L3 was developed as an improved biomarker, particularly for recurrence prediction [
2]. Therefore, such a shortfall puts into focus reliable biomarkers with the ability to detect recurrence risk in an attempt to start appropriate interventions and bespoke treatment.
GULP1 (GULP PTB domain-containing engulfment adaptor 1) is an adaptor protein that harbors a phosphotyrosine-binding (PTB) domain, which is an important domain of GULP1 required for the interaction of proteins with other proteins. The PTB domain in GULP1 enables phosphotyrosine motif binding and is of great significance in cellular signaling and endocytosis [
3]. GULP1 has been implicated in various diseases and cancers. In Alzheimer’s disease, it promotes the production of amyloid-β peptide by interacting with APP [
4]. Moreover, GULP1 acts as a downstream effector of estrogen receptor-β4, regulating cisplatin sensitivity in bladder cancer [
5]. These functions highlight the importance of GULP1 in the development of cancer and the response to treatment.
In order to address important issues and enhance patient outcomes, Kim et al. [
6] present GULP1 as a possible biomarker for predicting HCC recurrence in this issue of
Clinical and Molecular Hepatology. They developed a 15-gene risk score model with superior performance to the 7-gene models currently available for HCC recurrence in the GSE14520, GSE114564, and TCGA LIHC datasets. Of the genes investigated, GULP1 was one of the leading candidates that demonstrated equivalent predictive capability as the whole model when independently tested. The primary origin of GULP1 expression was confirmed as hepatocytes, indicating its hepatocyte-specific role in HCC. Notably, the function of GULP1 in HCC appears to be distinct from that in the other 33 TCGA cancers. For example, knockdown of GULP1 in urothelial carcinoma of the bladder might promote tumor cell proliferation in vitro and enhance tumor growth in vivo [
7]. Additionally, GULP1-positive hepatocytes have transcriptional enrichment in important carcinogenic pathways, including as the KRAS, hypoxia, and EMT pathways that are essential for the advancement of HCC. This draws attention to a particularly fascinating feature: important carcinogenic processes are transcriptionally associated with hepatocyte clusters exhibiting strong GULP1 expression.
The research also uncovers the biological mechanisms linking GULP1 to HCC recurrence. It was found that high expression of Wnt in HCC can increase tumor progression, while aquaporin 9 impairs Wnt/β-catenin signaling to suppress invasion and epithelial-mesenchymal transition (EMT) in tumor cells [
8]. The authors discovered that GULP1 promotes HCC tumor growth, proliferation, and invasiveness by activating β-catenin signaling—a pathway central to EMT and metastasis, both key contributors to recurrence. GULP1 expression was found to be highest in PLC/PRF/5 and Huh-7 cells. GULP1 downregulation repressed cell proliferation, growth, and clonogenic potential, whereas re-expression of GULP1 preserved migratory capacity. In vivo models of GULP1 downregulation and overexpression in mice showed that reducing GULP1 expression diminishes tumor burden and metastatic potential, whereas increased levels worsen these effects. TCF3 directly bound and regulated the GULP1 promoter. ARF6 downregulation lowered β-catenin and TCF3 binding capacity to the GULP1 promoter. TCF3 binding affinity to the GULP1 promoter region was different when GULP1 expression was controlled. GULP1, in general, stabilizes ARF6-GTP such that β-catenin can move into the nucleus and increase oncogenic activity through TCF3 binding at its promoter.
The clinical relevance of GULP1 is also highlighted by its value as a non-invasive biomarker for diagnostic and prognostic purposes. In series of patients, serum GULP1 level outperformed AFP—the current gold standard marker—in differentiating HCC from non-tumoral processes (AUC 0.833 vs. 0.540) and recurrence prediction (C-index 0.745 in tissue vs. 0.663 for AFP). Kaplan-Meier analyses consistently linked elevated GULP1 expression with poorer recurrence- free survival, confirming its prognostic role. The authors also contrasted serum GULP1 levels in stratified groups, such as hepatitis B virus, hepatitis C virus, and alcohol- associated HCC. GULP1 expression was higher in HCC groups compared to non-HCC groups. In addition, GULP1 could distinguish between non-tumor samples and non-HCC liver tumors, also outperforming AFP. These findings suggest that GULP1 can enhance early detection and risk stratification, surpassing the limitations of AFP’s sensitivity and specificity.
The implications of this research extend to treatment. GULP1 is involved in a number of diseases through a variety of mechanisms, including PPAR signaling [
9]. The oncogenic activity of GULP1 in HCC and its interaction with Wnt/β-catenin, Notch, and Hedgehog pathways (as evidenced by gene set enrichment analysis) offer avenues for targeted therapy. Combining GULP1 with existing biomarkers like AFP or emerging markers such as glypican-3 may improve predictive accuracy. Additionally, therapeutic strategies against GULP1-mediated ARF6-β-catenin signaling may give a new beam of hope in managing recurrent HCC.
FOOTNOTES
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Authors’ contribution
PDL: Original Drafting; NW: Writing and Review & Editing.
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Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
epithelial-mesenchymal transition
GULP PTB domain-containing engulfment adaptor 1
REFERENCES
- 1. Llovet JM, Pinyol R, Yarchoan M, Singal AG, Marron TU, Schwartz M, et al. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol 2024;21:294-311.
- 2. Norman JS, Li PJ, Kotwani P, Shui AM, Yao F, Mehta N. AFPL3 and DCP strongly predict early hepatocellular carcinoma recurrence after liver transplantation. J Hepatol 2023;79:1469-1477.
- 3. Chau DD, Yung KW, Chan WW, An Y, Hao Y, Chan HE, et al. Attenuation of amyloid-β generation by atypical protein kinase C-mediated phosphorylation of engulfment adaptor PTB domain containing 1 threonine 35. FASEB J 2019;33:12019-12035.
- 4. Chau DD, Yu Z, Chan WWR, Yuqi Z, Chang RCC, Ngo JCK, et al. The cellular adaptor GULP1 interacts with ATG14 to potentiate autophagy and APP processing. Cell Mol Life Sci 2024;81:323.
- 5. Tatenuma T, Matsukawa T, Goto T, Jiang G, Sharma A, Najafi MAE, et al. GULP1 as a downstream effector of the estrogen receptor-β modulates cisplatin sensitivity in bladder cancer. cancer genomics proteomics 2024;21:557-565.
- 6. Kim HS, Yoon JH, Choi JY, Yoon MG, Baek GO, Kang M, et al. GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma. Clin Mol Hepatol 2025;31:914-934.
- 7. Hayashi M, Guida E, Inokawa Y, Goldberg R, Reis LO, Ooki A, et al. GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma. Sci Signal 2020;13:eaba0443.
- 8. Xue W, Yang L, Chen C, Ashrafizadeh M, Tian Y, Sun R. Wnt/β-catenin-driven EMT regulation in human cancers. Cell Mol Life Sci 2024;81:79.
- 9. Kim SY, Park SY, Kim JE. GULP1 deficiency reduces adipogenesis and glucose uptake via downregulation of PPAR signaling and disturbing of insulin/ERK signaling in 3T3-L1 cells. J Cell Physiol 2024;239:e31173.
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